NO752837L - - Google Patents

Description

PHOSPHORUS COMPOUNDS

The present invention relates to phosphorus compounds, namely dienyl phosphate of the general formula

wherein and R'^ means lower alkyl, aryl or benzyl and R^, R^ °<3 R^ hydrogen or lower alkyl, and 1,4-cycloaddition products of the general formula

wherein R^, R'-^R3°9R4^ are as defined above, and Z prepares the residue to a dienophilic compound.

IN

The compounds of formula I and V have anthelmintic properties and

are therefore applicable as anthelmintics.

The term "lower alkyl" refers to straight chain alkyl groups of 1-5 carbon atoms. The term "aryl" refers to phenyl, as with lower alkyl, halogen (fluorine, chlorine and bromine), nitrogen. or lower alkoxy (with 1-5 carbon atoms) can be single or multiple substituted.

Dienyl phophate is prepared in formula I in the s-cis form for the sake of simplicity, but this does not necessarily mean the real geometric conformation.

Preferred compounds of formula I are those in which R and R' are methyl or ethyl and R', R' and R' are hydrogen. Particularly preferred are dimethyl (1,3-butadiene-2-yl)-phosphate (or dimethyl-1-vinyl vinyl phosphate), diethyl (1,3-butadiene-2-yl)-phosphate

(or diethyl-1-vinyl vinyl phosphate).

The compounds of formula I and V can be prepared according to the invention by reacting the enolate of a compound of the general formula

in which R 2 , R 3 and R 4 have the meanings given above, with a halophosphate of the general formula

IN

in which R1 and R'^ have the meaning indicated above

and Y produces chlorine, bromine or iodine,

or that 3,4-dichlorobutanone is reacted with a phosphite of the general formula

wherein R^ has the above meaning,

whereby a compound is obtained in the last reaction

of formula I, wherein R^, R^ °9 R 4 produces hydrogen and R^ and

R'-^ are identical, and that, if desired, a compound of formula I is converted with a dienophilic compound into a compound of formula V.

The compounds of formula I, wherein R^, R^0<3 R^ produces hydrogen and wherein R^^ and R'^ are identical are obtained by reacting 3,4-dichlorobutanone with a phosphite of formula II.

Examples of such phosphites are: trimethyl phosphite, triethyl phosphite, tri-(n-propyl) phosphite, tri-(n-butyl) phosphite, tri-(n-pentyl) phosphite, triphenyl phosphite and tribenzyl phosphite. Particularly preferred phosphites are trimethyl phosphite and triethyl phosphite.

The reaction of the 3,4-dichlorobutanone with the phosphite of formula II

was appropriately carried out in the absence of additional solvents. If desired, however, inert organic solvents can also be used, such as e.g. hydrocarbons, such as hexane, benzene

and toluene, or halogenated hydrocarbons, such as dichloromethane and the like.

The reaction appears to proceed in two steps. The first step takes place quickly at temperatures of approx. 0 to approx. 5o°C, preferably approx. 2o to approx. 3o°C, whereby the alkyl chloride R^Cl is evolved.

In the second reaction step, hydrogen chloride is eliminated. This occurs when heated to approx. 5o to approx. 15o°C, and is conveniently carried out by distillation of the reaction mixture, preferably under reduced pressure. In this way, a final product of formula I is obtained, in which R 1 , R 3 and R 3 are hydrogen.

i In order to promote the elimination of the hydrogen chloride during the distillation, a small amount (for example less than 1 mol%) of a Lewis acid, for example aluminum chloride, is suitably added.

In order to prevent the polymerization of the diene of formula I during the distillation, it is appropriate to add a small amount (for example 1 mol% or less) of a polymerization inhibitor, for example hydroquinone.

The production of dienyl phosphates from 3,4-dichlorobutanone and phosphite is to be regarded as unexpected in view of the fact that the same reaction using 3,4-dibromobutanone as known only gives methyl-vinyl-ketone (J.P. Schroeder, et al., J. Org,

Chem. 35, 3181 (1970)).

The total number of compounds covered by formula I can be prepared from a conjugated ketone of the formula

and that in the manner already explained above, by reacting an enolate of one compound of formula III with a halogenophosphate of formula IV.

The enolate of a compound of formula III, i.e. a compound

of the formula

in which R2, R3 and R4 have the meaning indicated above

and M<+>represents the sodium, potassium or lithium ion, may be prepared by reacting the compound of formula III

met a strong, organic, soluble alkali metal amide base in an inert organic solvent at low temperature. Preferred bases are alkali metal alkylamide and alkali metal cycloalkylamide such as lithium N-cyclohexyl-N-isopropyamide, lithium cyclohexyl amide and alkali metal silylamide, such as sodium bis(trimethylsilyl)amide. Suitable inert organic solvents for carrying out this reaction are, for example, organic ethers, such as diethyl ether, dioxane and tetrahydrofuran, as well as hydrocarbons, such as hexane and heptane and the like.

The enolate thus obtained is then reacted with a halogen phosphate of the formula IV. Both the formation of the enolate and the subsequent reaction with the halogen phosphate can conveniently be carried out at a reduced temperature, for example at approx. -80- approx. -2o°C.

A particularly preferred temperature range is between approx. -65 to approx. -75°C.

After the usual work-up, the product of formula I is isolated

and cleaned. A particularly preferred purification method consists in distillation under reduced pressure.

As examples of the compound of formula I can be mentioned: dimethyl-(1,3-butadiene-2-yl)-phosphate

diethyl-(1,3-butadiene-2-yl)-phosphate

dimethyl-(1,3-pentadien-3-yl)-phosphate

diethyl-(1,3-pentadien-3-yl)-phosphate

dimethyl-(1,3-pentadien-2-yl)-phosphate

diethyl-(1,3-pentadien-2-yl)-phosphate

dimethyl-(3-methyl-1,3-butadiene-2-yl)-phosphate diethyl-(3-methyl-1,3-butadiene-2-yl)-phosphate dimethyl-(3-methyl-1,3-pentadiene -2-yl)-phosphate

* diethyl-(3-methyl-1,3-pentadien-2-yl)-phosphate dimethyl-(3-methyl-1,3-pentadien-3-yl)-phosphate diethyl-(2-methyl-1,3- pentadien-3-yl)-phosphate dimethyl-(3-ethyl-1,3-hexadien-2-yl)-phosphate diethyl-(3-ethyl-1,3-hexadien-2-yl)-phosphate dimethyl-(2 -ethyl-1,3-hexadien-3-yl)-phosphate diethyl-(2-ethyl-1,3-hexadien-3-yl)-phosphate dimethyl-(4-methyl-3,5-decadien-5-yl )-phosphate diethyl-(5-ethyl-3,5-nonadien-4-yl)-phosphate

dimethyl-(4-methyl-2,4-decadien-3-yl)-phosphate diethyl-(4-propyl-3,5-nonadien-5-yl)-phosphate.

The compounds of formula I are substituted dienes and readily undergo Diels-Alder reaction with dienophilic compounds to form

of 1,4-cycloaddition products (enol phosphates) of formula V.

In the following, a dienophilic compound is understood to mean an unsaturated organic compound, which enters into a 1,4-cycloaddition reaction with a conjugated diene. Most dionephilic compounds have a non-aromatic unsaturated bond (double bond or triple bond), which is directly substituted with at least one electronegative group. Examples of such dienophilic compounds are: nitriles, e.g. tetracyanethylene and acrylonitrile, aldehydes e.g. crotonaldehyde and acrolein, acids, e.g. acrylic acid, cinnamic acid, maleic acid and fumaric acid, ester, e.g. ethyl acrylate, dimethyl maleate, dimethyl fumarate, diethyl acetylene dicarboxylate, diethyl azodicarboxylate, anhydrides, e.g. maleic anhydride and citraconic anhydride, imides, e.g. N-phenylmaleimide, 4-phenyl-1,2,4-triazoline-3,5-dione and p-phenylazomaleinanil, nitroso compounds, e.g. nitrosobenzene, nitrogen compounds, e.g. p-nitrostyrene and 1-nitropropene, ketones, e.g. methyl vinyl ketone and the like.

in

The preparation of Diels-Alder adducts from compounds of formula I takes place in the usual way for such Diels-Alder reactions. Mon

can thereby work in the absence of a solvent or

in the presence of an inert organic solvent, whereby examples of inert organic solvents may be mentioned: hydrocarbons, such as hexane, heptane, benzene and tolaene, halogenated hydrocarbons, such as dichloromethane, organic ethers, such as diethyl ether, tetrahydrofuran and dioxane and the like. The Diels-Alder reaction can be carried out within a wide temperature range, for example'

between c* a. 0 and approx. +15o oC. A preferred temperature range is between approx. 2o and approx. 7o°C.

As mentioned above, the dienyl phosphate of formula I can be used as an anthelmintic. Furthermore, the enol phosphate of formula V also has an anthelmintic effect. The compounds of formula I are thus also usable as intermediates for the preparation of the compounds of formula V.

In particular, the compounds according to the invention are useful for combating Ascaris suum infections, whereby they are suitably administered orally (addition of o.1% to f6r.).

The compounds of formula I are also, as shown above, useful as reagents for Diels-Alder reactions.

Furthermore, the compounds of formula I serve as valuable monomers, which can be polymerized either with themselves or with other monomers, thereby obtaining complex polymer molecules with a large number of application possibilities, for example compounds that are useful as fire hazard inhibitors.

EXAMPLE 1

166 g of triethyl phosphite are soaked in an ice bath and then 140 g of 3,4-dichlorobutanone are added. The mixture is stirred for 2 hours at 0° and then for 20 hours at room temperature. After 0.5 g of hydroquinone and 0.5 g of aluminum chloride have been added, the mixture is distilled under reduced pressure, whereby 34.4 g of pure diethyl-(1,3-butadiene-2-yl)-phosphate hemihydrate is obtained, which boils at 91-92°/2 mmHg.

The 3,4-dichlorobutanone used in the above procedure can be obtained as follows:

chlorine i

Mon. lead/a solution of 140 g of methyl vinyl ketone in 600 ml of chloroform under ice-cooling. After 142 g of chlorine had been absorbed, the chloroform formed is evaporated (bath temperature 35°), whereby 290 g of slightly contaminated 3,4-dichlorobutanone is obtained, which can be used without any further purification.

EKS EMPEL 2

28.6 g of trimethylphosphite is reacted with 32 g of 3,4-dichlorobutanone analogously to example 1. After the distillation, pure dimethyl-(1,3-butadiene-2-yl)-phosphate is obtained, which boils at 79-83°/l .5mmHg.

UV 22o nm (6 1652o) in methanol.

EXAMPLE 3

A solution of 2.15 g of diethyl-(1,3-butadiene-2-yl)-phosphate

1.28 g of tetracyanethylene are added to 10 ml of tetrahydrofuran under a nitrogen atmosphere. The yellow solution obtained is allowed to stand at room temperature for 2 days and then evaporated. The remaining syrup is taken up in ethyl acetate, petroleum ether is added until darkening occurs and the mixture is allowed to stand for 5 days at 0°. After filtration, 2.log g 1,1,2,2-tetracyano-4-(o,o-diethylphosphoryloxy)-cyclohexene is obtained with a m.p. at 97-98°. After recrystallization from a mixture of ethyl acetate and petroleum ether, the pure substance is obtained in the form of long prisms and short flakes with a m.p. at 98°.

IR (petrolatum): max 1665, 126o and lo45 cm<-1>.

in

NMR (CDCl ), T* : 8.61 (triplet, 6H), 6.69 (multiplet, 4H), 5.75 (quintet, 4H), 4.12 (multiplet, 1H).

EXAMPLE 4

A mixture of 0.98 g of maleic anhydride and 1.78 g of dimethyl-(1,3-butadiene-2-yl)-phosphate in 50 ml of benzene was stirred at room temperature for 20 hours. The viscous mass obtained after evaporation was crystallized from ethyl acetate/petroleum ether, thereby obtaining 0.810 g of 4-(o,o-dimethylphosphoryloxy)-cyclohex-4-éh-cis-1,2-carboxylic acid anhydride with a m.p. on

71-72°. After recrystallization from the same solvent system, prisms are obtained, which melt at 73-74°.

IR (petrolatum): 185o, 1785, 167o, 1275 and 1045 cm<-1>.

EXAMPLE EL 5

To a solution of 3.24 g of nitrosobenzene in 150 ml of methylene chloride is added 6.25 g of diethyl-(1,3-butadiene-2-yl)-phosphate.

The mixture is allowed to stand for 20 hours at room temperature and then evaporated. The remaining crude product is purified on a silica gel column and eluted with ethyl acetate/petroleum ether (1:2), whereby 7.1 g of faintly colored 2-phenyl-4-(o,o-diethyl-phosphoryloxy)-3,6-dihydro- 2H-1,2-oxazine.

UV (ethanol) : 24o (E 788o) , 282 nm (£, 85o).

NMR (CDCl-j)<1>^: 6.15 (s), 5.50 (m), 4.25 (m).

EXAMPLE 6

1.78 g of dimethyl-(1,3-butadiene-2-yl)-phosphate are dissolved in 30 ml of methyl vinyl ketone and the solution is stirred for 20 hours at 65°C

in a nitrogen atmosphere. The excess of methyl vinyl ketone is then evaporated and 3.60 g of a crude product is obtained which is purified by soil chromatography.

The position of the acyl peaks in the NMR spectrum shows that the product is

a mixture of isomers, namely of l-acetyl-3-(o,o-dimethyl-phosphoryloxy)-cyclohex-3-ene and l-acetyl-4-(o,o-dimethylphosphoryl-oxy)-cyclohex-3- one.

EXAMPLE 7

A solution of equivalent amounts of diethyl-(1,3-butadiene-2-yl)-phosphate and 4-phenyl-1,2,4-triazoline-3,5-dione-

let stand for 2o hours at room temperature. The solvent is then removed and the residue is crystallized from benzene/hexane, whereby colorless crystals of 2-phenyl-6-(o,o-di-ethylphosphoryloxy)-2,3,5,8-tetrahydro-lH-s are obtained -triazolo-,/I, 2a_7 pyridazine-1,3-dione with a m.p. at 84-85°C.

E XAMPLE" 8

A solution of 31 g of N-cyclohexyl-N-isopropylamide in 400 ml of tetrahydrofuran is cooled to -70°. While stirring, 0.22 mol of n-butyllithium in hexane is added dropwise over the course of 5 minutes. 14 g of methyl vinyl ketone are then added over the course of 20 minutes and then 37.8 g of diethyl chlorophosphate over the course of 10 minutes. The solution is then left to stand for 90 minutes. at -7o°, stand where it is allowed to warm up to room temperature. It is then diluted with methylene chloride and then washed with 5% aqueous sodium bicarbonate solution, 1 N aqueous hydrochloric acid and 10% aqueous sodium chloride solution. The organic phase is then dried, evaporated and the residue distilled, whereby 22-25 g of diethyl-(1,3-butadiene-2-yl)-phosphate are obtained, which boils at 7 4°/o.5 mmHg.

Claims (1)

1. Process for the preparation of dienyl phosphates of the general formula wherein R-^ and R1^ mean lower alkyl, aryl or benzyl and R^, R^ 0<3 R4 means hydrogen and lower alkyl, and of 1,4-cycloaddition products thereof of the general formula "wherein R'^ , R'^/ R2' R3°^ R4 ^are ^one specified above meaning and Z is a residue of a dienophilic compound, characterized by converting the enolate of a compound of the general formula wherein 1*2, R^ and R4 have the above meaning, with a halogenophosphate of the general formula ; in which R^ and R<1>^ have the meaning indicated above, and Y means chlorine, bromine or iodine, or that one reacts 3,4-dichlorobutanone with a phosphite of the general formula; in which R^ has the above meaning, whereby one obtains in the last reaction a compound of formula I, in which R2/R-^° g R4 produces hydrogen and R^ and R1^ are identical, and that, if desired, one reacts a compound of formula I with a dienophilic compound to a compound of formula V.;2. Process according to claim 1, characterized by using 3,4-chlorobutanone or a compound of formula IV, in which R^ , R' 1 produce methyl or ethyl, as starting materials.;3. Process according to claim 1 or 2, characterized in that a starting material is used, in which R 2 , R 1 and R 4 produce hydrogen.; 4. Method according to claim 1, 2 or 3, characterized in that 3,4-dichlorobutanone is reacted with a compound of formula II fost at ca-, o to ca. • 5o o C and sener1 e during heating to approx. 5o to 15o oC.;5. Method according to claim 4, characterized in that one uses an initial temperature of approx. 2o to approx. 3o°C.; 6. tProcedure according to claim 4, characterized in that the heating is carried out as distillation.;7. Method according to one of claims 4-6, characterized in that the reaction is carried out in the absence of an additional solvent.;8. Method according to one of claims 1-3, characterized in that carrying out the reaction of an enolate of a compound of formula III with a halogen phosphate of formula IV at a low temperature, preferably between approx. -2o and approx. -8o°C, especially between approx. -65 and -75°C.;9. Process according to claim 8, characterized in that the lithium enolate is used as the enolate of a compound of formula III.;10. Process for the production of pharmaceutical preparations with anthelmintic action, characterized by mixing a dienyl phosphate of the general formula; in which R^ and R1 mean lower alkyl, aryl or benzyl and R2 , R3 and R^ mean hydrogen or lower alkyl, In or a 1,4-cycloaddition product thereof of the general formula ;in which Rj^, R'^/ R2' R3°9 R4 *iar ^a meaning given above, and Z prepares the remainder of the dienophilic compound, with a pharmaceutically acceptable carrier material. 11. Pharmaceutical preparation with anthelmintic action, characterized in that it contains a dienyl phosphate of the general formula wherein R 1 and R 1 are lower alkyl, aryl or benzyl and R 2 , R 3 and R 3 are hydrogen or lower alkyl, or a 1,4-cycloaddition product thereof of the general formula wherein R 1 , R 1 , R 1 , R 3 , R 4 , are as defined above and Z forms the residue of a dienophilic compound, together with a pharmaceutically acceptable carrier material. ' 12. Compounds of the general formula in which R-^ and R^ mean lower alkyl, aryl or benzyl and R 2 , R 3 and R 4 mean hydrogen or lower alkyl, and 1,4-cycloaddition products thereof of the general formula in which R^ , R'-^ R3°9 R4 have ^an above stated meaning and Z means the residue of a dienophilic compound. 13. Compounds according to claim 12, in which R^ and R'^ mean methyl or ethyl. 14. Compounds according to claims 12 or 13, in which R 2 , R 1 and R 2 are hydrogen. 15. Dimethyl-(1,3-butadiene-2-yl)-phosphate. 16. Diethyl-(1,3-butadiene-2-yl)-phosphate. 17. 1,1,2,2-Tetracyano-4-(o,o-diethylphosphoryloxy)-cyclohex-4-ene. 18. 4-(o,o-dimethylphosphoryloxy)-cyclohex-4-ene-cis-1,2-carboxylic acid anhydride. 19. 2-Phenyl-4-(o,o-diethylphosphoryloxy)-3,6-dihydro-2H-1,2-oxazine. 20 . 1-acetyl-3-(o,o-dimethylphosphoryloxy)-cyclohex-3-ene. 21. 1-acetyl-4-(o,o-dimethylphosphoryloxy)-cyclohex-3-ene. 22. 2-Phenyl-6-(o,o-diethylphosphoryloxy)-2,3,5,8-tetrahydro-1H-s-triazolo-[1,2a]-pyridazine-1,3-dione.